To understand the nature of interrelationships between carcinogenesis and DNA metabolism, chromosome structure, and biological reagents, in vivo and in vitro approaches are being used in model systems. Evidence has been accumulated that human cells are not transformed to the malignant state by chemical, physical, or viral carcinogenic agents that are effective with animal cells. Therefore, a multifaceted cocarcinogenesis approach is being used with human cells to overcome the genome stability or genetic suppression of transformation. Human fibroblasts and prokeratinocytes derived from foreskin have been transfected with recombinant HPV 16 DNA. Stable, intact extrachromosomal HPV 16 sequences have been demonstrated in transfected cells which acquire an indefinite life span and anchorage independent growth. Studies wiht cervical carcinomas and NIH/3T3 transfected cells have shown the importance of integration of papilloma sequences for tumorgenicity. In HeLa cells four chromosome sites contain HPV 18 sequences. Three of these are also associated with fragile sites. Moreover, this is the first demonstration of integration of a human DNA virus near sites of proto-oncogenes. Two stages of transformation were observed in HPV 16-transfected NIH/3T3 cells. Transfected cells have a higher proportion of integrated HPV DNA and decreased HPV 16 expression when the cells become tumorgenic. A common chromosome change associated with a common chromosome fragile site was found in eight of nine malignant mesotheliomas derived from asbestos exposed patients. Because no proto-oncogene has been identified at this location, an important suppressor or regulatory gene may have been lost or inactivated. Preneoplastic and tumorgenic guinea pig cells have been analyzed for oncogenes. Activation of N-ras is associated with acquisition of tumorgenicity. The identical AT to TA transversion was found in N-ras in five tumorgenic lines initiated by various carcinogens. This mutation was not induced by the mutagenic activity of the initiating carcinogen.